Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms.

Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2.

Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson's disease (PD), with 10-30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity.

Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone.

A hallmark of Alzheimer's disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD.

The Impact of Adverse Childhood Experiences on Symptom and Performance Validity Tests Among a Multiracial Sample Presenting for ADHD Evaluation.

Objective: Adverse childhood experiences (ACEs) are commonly reported in individuals presenting for attention-deficit hyperactivity disorder (ADHD) evaluation. Performance validity tests (PVTs) and symptom validity tests (SVTs) are essential to ADHD evaluations in young adults, but extant research suggests that those who report ACEs may be inaccurately classified as invalid on these measures. The current study aimed to assess the degree to which ACE exposure differentiated PVT and SVT performance and ADHD symptom reporting in a multi-racial sample of adults presenting for ADHD evaluation.